Precise control of gene transcription patterns, mediated by chromatin structural changes, is essential for cell identity preservation that is disrupted in cancer cells. The CoREST complex, a multi-protein complex of histone-modifying enzymes, functions as a transcriptional co-repressor by facilitating formation of repressive chromatin. The CoREST complex contains two key histone modifying enzymes, lysine-specific histone demethylase 1 (LSD1) and histone deacetylase 1 and 2 (HDAC1 and HDAC2) held together by the CoREST scaffolding protein. These enzymes are typically up-regulated in cancer, suggesting the CoREST complex is a specific target for cancer therapy. The goal of this proposed study is to molecularly define the CoREST complex as a therapeutic target for cancer. We recently developed a small molecule inhibitor (corin2) of the CoREST complex. Corin2 is a dual inhibitor of LSD1 and HDACs1/2 in the CoREST complex and shows high potency anti-proliferative effects against many cancer cell types when screened against the NCI 60 panel, with particular efficacy versus human melanomas. Our preliminary data suggests that the CoREST complex activates c-MYC/E2F-stimulated target genes associated with cell cycle progression and proliferation. In contrast, genes encoding the BMP/SMAD membrane-bound ligand-dependent nuclear receptors, which are known for promoting cellular differentiation, are transcriptionally silenced by the CoREST complex. The anti- proliferative role of the TGF-?/BMP-mediated SMAD signaling pathway is well documented; however, this function is often lost in many cancer cells. Here, we hypothesize that the CoREST complex induces disruption of BMP/SMAD driven anti-proliferative/differentiation signals resulting in increased transcriptional activation of the MYC/E2F-dependent proliferation gene network. In this way, blocking the CoREST/MYC proliferative gene transcription network circuit is expected to be an effective strategy in cancer. To test this hypothesis, we will perform the following aims using melanoma as a target cancer model: 1) analyze genome-wide effects of corin2 to discover the CoREST complex target gene signature and its correlation with the c-MYC/E2F target transcription network, 2) define the role of the CoREST complex in BMP/SMAD signaling and the switch from a differentiation/tumor- suppressive phenotype to cell growth phenotype, 3) evaluate corin2 as an epigenetic anti-tumor agent by targeting the transcriptional regulatory mechanisms of the c-MYC/E2F transcription network. To accomplish these aims, we will use the small molecule CoREST inhibitor, corin2, as well as a series of chemically-related analogs; a genetically engineered mouse melanoma model; and human melanoma tissue specimens. These proposed studies will extend our knowledge of the chromatin repressive CoREST complex and its roles in regulating a cell proliferative gene transcription network. In this manner, this proposal will provide a mechanistic rationale for the development of a novel therapeutic strategy targeting epigenetic malignancy-associated pathways in melanoma and other cancers.